Our overall goal is to understand the process of the generation of long-term humoral immunity. Long-lived plasma cells and memory B cells are the primary cellular components of long term humoral immunity, and as such are critically important for protection against many infectious diseases and are key components of the protection afforded by most vaccines. Germinal centers are the critical sites for the development of long term humoral immunity in the form of antigen-specific memory B cells and long-lived plasma cells. CD4 T cells are essential for germinal center function. Therefore it is vital to understand the role of CD4 T cells in germinal centers to understand how to better generate long term humoral immunity to viruses. Importantly, we now have an excellent system to examine this process, since we have shown that SAP (SLAM-associated protein) plays a central role in CD4 T cell help at the germinal center stage for the development of long term humoral immunity after a viral infection (Crotty et al., Nature 2003;Crotty and colleagues J. Immunology 2007). We also know that this critical function for SAP is conserved in humans. The experiments proposed herein are designed to answer pivotal questions regarding T cell help to B cells and the generation of long-term humoral immunity. This knowledge will illuminate a central process of adaptive immunity (the germinal center reaction and the generation of immunological memory) and help accelerate vaccine discovery (as a primary goal of vaccines is generation of memory B cells and long-term antibody production). Our studies focus heavily on antiviral immune responses because 1) SAP-deficiency results in an lethal susceptibility to infectious disease in humans, demonstrating that SAP is a crucial mediator of antiviral immune responses, and 2) the purpose of virtually all vaccine development is the prevention/control of infectious diseases.
Aim 1. What are the functional characteristics of germinal center / follicular helper CD4 T cells (TFH)? How do they drive strong antiviral antibody responses and the development of immunological memory? Why is SAP critical? We want to understand?in cellular and molecular detail?what, where, and how CD4 T cells in the follicle drive, sustain, and control the germinal center reaction and the generation of long-lived plasma cells and memory B cells.
Aim 2. SAP and ICOS: What is the link and what are their respective roles in germinal center development? Aim 3. Which SLAM-family receptor on CD4 T cells is critical for signaling germinal center help? Given the varied inputs and outputs of the SAP signaling pathway, it is unclear what SAP-dependent receptor is critical for signaling the downstream T cell help functions key for germinal center help.

Public Health Relevance

, Relevance. It is critical to understand the generation and maintenance of long term humoral immune responses (antibodies) in order to design better vaccines that can protect people long term from infectious diseases. It is also important to understand the human genetic disease XLP (X-linked lymphoproliferative disease), to potentially identify therapies for individuals with this disease, and to apply this knowledge to ameliorating other, related, human immune disease processes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Immunity and Host Defense Study Section (IHD)
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Ferguson, Stacy E
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La Jolla Institute
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Chen, Runqiang; BĂ©langer, Simon; Frederick, Megan A et al. (2014) In vivo RNA interference screens identify regulators of antiviral CD4(+) and CD8(+) T cell differentiation. Immunity 41:325-38
Xiao, Nengming; Eto, Danelle; Elly, Chris et al. (2014) The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells. Nat Immunol 15:657-66
Crotty, Shane (2014) T follicular helper cell differentiation, function, and roles in disease. Immunity 41:529-42
Boettler, Tobias; Choi, Youn Soo; Salek-Ardakani, Shahram et al. (2013) Exogenous OX40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular Th cell differentiation and diverts CD4 T cells into the effector lineage by upregulating Blimp-1. J Immunol 191:5026-35
Choi, Youn Soo; Yang, Jessica A; Crotty, Shane (2013) Dynamic regulation of Bcl6 in follicular helper CD4 T (Tfh) cells. Curr Opin Immunol 25:366-72
Hu, Joyce; Havenar-Daughton, Colin; Crotty, Shane (2013) Modulation of SAP dependent T:B cell interactions as a strategy to improve vaccination. Curr Opin Virol 3:363-70
Choi, Youn Soo; Eto, Danelle; Yang, Jessica A et al. (2013) Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J Immunol 190:3049-53
Choi, Youn Soo; Yang, Jessica A; Yusuf, Isharat et al. (2013) Bcl6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory. J Immunol 190:4014-26
Salek-Ardakani, Samira; Choi, Youn Soo; Rafii-El-Idrissi Benhnia, Mohammed et al. (2011) B cell-specific expression of B7-2 is required for follicular Th cell function in response to vaccinia virus. J Immunol 186:5294-303
Yusuf, Isharat; Kageyama, Robin; Monticelli, Laurel et al. (2010) Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J Immunol 185:190-202

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